Beta-arrestin 2 is required for lysophosphatidic acid-induced NF-kappaB activation.
Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-kappaB. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-kappaB is not fully defined. In this work, we found that beta-arrestin 2, but not beta-arrestin 1, is required for LPA-induced NF-kappaB activation and interlukin-6 expression. Mechanistically, we found that beta-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-kappaB activation, suggesting that beta-arrestin 2 may recruit CARMA3 to LPA receptors. Although beta-arrestin 2 deficiency did not affect LPA-induced IKKalpha/beta phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKKalpha/beta activation but not for the inducible phosphorylation of IKKalpha/beta. Together, our results provide the genetic evidence that beta-arrestin 2 serves as a positive regulator in NF-kappaB signaling pathway by connecting CARMA3 to GPCRs.
Sun
Jiyuan
J
Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lin
Xin
X
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D008246:Lysophospholipids; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C032881:lysophosphatidic acid